Anti-HIV Natural Products from the plants Destributed in the Northern Part of Japan

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As a part of the structure-activity relationship study of the potent anti-HIV agent 3-Ο-(3', 3'-dimenthyl)-succinyl-betulinic acid(DSB), 3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity, 3-αDiglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity(EC_<50> 0.24 μM, TI 728). However, replacing the ester group at C-3 in DSB and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in is essential for potent anti-HIV activity.Four isomers of 3,28-di-Ο-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-Ο-(3', 3'-Dimethylsuccinyl)-28-Ο-(2", 2"-dimethylsuccinyl)-betulin was the most potent anti-HIV compound with an EC_<50> value of 0.00087 μM and a TI value of 42,400.3-Ο-Acyl-ursolic acids were prepared and evaluated their anti-HIV activities, based on our previous finding that 3-Ο-acyl-betulinic acid and -oleanolic acid, especially 3-Ο-(3', 3'-dimethyl)-succinyl-betulinic acid, and -oleanolic acid demonstrated potent anti-HIV activities(EC_<50> < 0.00035 and 0.00086 μM, respectively, therapeutic index(TI) > 20,000 and 22,326, respectively), as well as the fact that ursolic acid(6)showed similar level of anti-HIV activity(EC_<50> 4,4μM)to that of oleanolic acid(EC_<50> 3.7 μM), though it was slightly toxic(IC_<50> 14.3 μM, T.I.3.3). 3-Ο-Diglycoryl-ursolic acid demonstrated relatively potent anti-HIV activity with an EC_<50> 0.31 μM, and a TI of 155.5. In contrast, 3-Ο-(3', 3'-dimethylsuccinyl)-ursolic acid, corresponding to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives displayed only a weak anti-HIV activity(EC_<50> 2.1μM, T.I.23.6).